The overall objectives of the studies proposed in this Program Project Application (PPA) are to explore the potential efficacies of using stem/progenitor cells and modified pancreatic islets as cellular therapies to restore endocrine pancreas function and to thereby cure diabetes mellitus. The motivation for this PPA is the fortuitous occurrence of several events: (1) the independent discoveries of pancreatic stem cells by three Harvard investigators, Dr. Susan Bonner-Weir (Joslin), Dr. Joel Habener (Massachusetts General Hospital), and Dr. Richard Mulligan (Childrens' Hospital); (2) the availability from Dr. Douglas Helton (Harvard University) of normalized pancreas cDNA arrays that contain all of the genes express in the pancreas; (3) the development by Dr. Dennis Sgroi (Massachusetts General Hospital) of a means to prepare gene expression profiling probes by Dr. Bennis Sgroi (Massachusetts General Hospital) of a means to prepare gene expression profiling probes from minuscule amounts of tissue obtained by laser capture microdissection; (4) the discovery by Dr. Melissa Thomas (Massachusetts General Hospital) of active hedgehog signaling in the islets of the adult pancreas and (5) the availability from Dr. Gordon Weir (Joslin) of high quality human islets from a preexisting islet transplantation core laboratory. The application proposes three scientific projects and two scientific cores that will work synergistically together to achieve the objectives. Project 1: Pancreas-derived stem/progenitor cells for the regeneration of beta cells (PI: Dr. Bonnor-Weir) has three aims: (1) analysis of distinct populations of duct-derived stem/progenitor cells; (2) gene expression profiling comparisons of human duct-derived versus islet derived stem/progenitor cells during their differentiation; (3) regeneration of beta-cells via transplantation of stem/progenitor cells in animal models of diabetes (rat partial pancreatectomy). Project 2: Modulation of pancreatic islets for transplantation (PI: Dr. Weir) has three aims: (1) evaluation of human islets by expression profiling; (2) determination of the fate of human islets after transplantation; (3) differentiation of transplanted stem/progenitor cells (NIPs, ductal progenitors, SP cells, and others. Project 3: Morphogen signaling during pancreatic islet development (PI: Dr. Thomas) has three aims: (1) mechanisms by which hedgehog signaling regulates expression of homeodomain protein IDX-1; (2) role of hedgehog signaling in the differentiation of pancreas-derived stem/progenitor cells into beta-cells; (3) hedgehog signaling in beta-cell development in vivo. The two scientific cores are: Core B: Islet isolation and transplantation (CD: Dr. Weir) and Core C: Laser capture microdissection and gene expression profiling (Co-CDs: Drs. Sgroi and Melton). All three projects will be heavy users of the two cores. In fact. The cores are the heart of the project, without which the objectives of the project could not be accomplished The two scientific cores are already established and running as components of the Harvard JDRF Islet Transplantation Center. In addition, all participants in this PPA application are members of one of the two NIDDK-funded Diabetes Endocrinology Research Centers (Joslin and MGH-based). An important aspect of this PPA is that the participants will be amongst the first to profile gene expression on cDNA arrays that incorporate all of the genes expressed in the pancreas and allow for determinations of the differences in genes expressed in healthy versus diseased islets and the genes expressed during the differentiation of stem/progenitor5 cells into beta-cells. This PPA proposes the initial studies on the way to providing a cure for diabetes via the approaches for regenerative medicine.